Multiple myeloma is a lymphoid cancer that is presently incurable. It is characterized by massive immunoglobulin secretion, accumulation of plasma cells in the bone marrow, bone loss, and associated elevation of IL-6 levels. In normal B cell terminal differentiation, homeostasis is maintained by cell cycle control and cell death. Our lack of understanding of the development of multiple myeloma reflects our inadequate knowledge regarding the primary mechanism of normal B cell terminal differentiation. The studies of malignant plasma cell generation have so far been accomplished using myeloma and plasmacytoma cell lines, without a normal reference. Recently, stimulation of EBV- immortalized human IgG-bearing lymphoblastoid cells with IL-6 has established the first in vitro B cell terminal differentiation system. It was found that IL-6-differentiated plasma cells rapidly die by apoptosis, following cell cycle arrest and reversal of EBV immortalization during B cell terminal differentiation. Apoptosis of human plasma cells, however, was controlled by mechanisms unlike the apoptotic pathway induced in B cells following ligation of Fas. In parallel, unpublished results further suggest that the development of plasmacytoma, the mouse counterpart of human multiple myelomas, results from deregulation of B cell expansion, in conjunction with failure of post-mitotic plasmacytoma cells to undergo cell death. Taking advantage of the unique combination of the IL-6 transgenic mouse model for plasmacytomagenesis, and the newly developed primary mouse B cell terminal differentiation system, the mechanisms by which primary plasma cells die, and plasmacytoma cells accumulate will be investigated. The two specific aims of the proposal are 1) to investigate the mechanism that underlies death of primary mouse plasma cells in vitro, by characterizing the biochemical mechanism of apoptosis and anti-apoptosis, and the requirement of caspase-3, and 2) to investigate the mechanism of death of plasmacytoma cells in vivo, and in vitro, by similar characterization of the biochemical mechanism of cell death, and to determine the molecular interaction between plasma cells and plasmacytoma cells with bone marrow stromal cells. The long term goal is to understand the molecular mechanism that underlies the pathogenesis of multiple myeloma. By completing these studies, new insight should be obtained into the control of normal B cell terminal differentiation and the generation of plasmacytoma through cell death, which should lead to a conceptual framework for future studies of the development of multiple myeloma in humans.